Basanta Benjamin, Nugroho Karina, Yan Nicholas L, Kline Gabriel M, Powers Evan T, Tsai Felix J, Wu Mengyu, Hansel-Harris Althea, Chen Jason S, Forli Stefano, Kelly Jeffrey W, Lander Gabriel C
Department of Integrative Structural and Computational Biology, Scripps Research, La Jolla, CA, USA.
Arzeda, Seattle, WA, USA.
Nat Struct Mol Biol. 2025 May;32(5):876-883. doi: 10.1038/s41594-024-01472-7. Epub 2025 Jan 22.
Transthyretin (TTR) is a natively tetrameric thyroxine transporter in blood and cerebrospinal fluid whose misfolding and aggregation causes TTR amyloidosis. A rational drug design campaign identified the small molecule tafamidis (Vyndamax) as a stabilizer of the native TTR fold, and this aggregation inhibitor is regulatory agency approved for the treatment of TTR amyloidosis. Here we used cryo-EM to investigate the conformational landscape of this 55 kDa tetramer in the absence and presence of one or two ligands, revealing inherent asymmetries in the tetrameric architecture and previously unobserved conformational states. These findings provide critical mechanistic insights into negatively cooperative ligand binding and the structural pathways responsible for TTR amyloidogenesis, underscoring the capacity of cryo-EM to identify pharmacological targets suppressed by the confines of the crystal lattice, opening uncharted territory in structure-based drug design.
转甲状腺素蛋白（TTR）是血液和脑脊液中一种天然的四聚体甲状腺素转运蛋白，其错误折叠和聚集会导致TTR淀粉样变性。一项合理的药物设计活动确定小分子tafamidis（Vyndamax）为天然TTR折叠的稳定剂，这种聚集抑制剂已获监管机构批准用于治疗TTR淀粉样变性。在这里，我们使用冷冻电镜研究了这种55 kDa四聚体在不存在和存在一个或两个配体的情况下的构象景观，揭示了四聚体结构中固有的不对称性以及以前未观察到的构象状态。这些发现为负协同配体结合以及导致TTR淀粉样变的结构途径提供了关键的机制见解，强调了冷冻电镜识别被晶格限制所抑制的药理学靶点的能力，为基于结构的药物设计开辟了未知领域。
